Wrist-watch back cases, systems and methods for measuring biomarkers

ABSTRACT

A wrist-watch back case for replacing existing back case of a timekeeping device or to be attached thereto is provided. The back case comprises a casing comprising a bottom wall and a side wall thereby defining an inner empty space, at least five openings at the bottom wall, an optoelectronic board, at least two paired radiation sources and at least one radiation detector. Methods for measuring biomarkers, systems and a watchband are also provided.

The present application claims the benefit and priority of U.S.62/641,299, filed on Mar. 10, 2018.

The present disclosure relates to devices, systems and methods formeasuring biomarkers, more specifically to devices, systems and methodsfor measuring biomarkers in a non-invasive manner.

BACKGROUND

One of the most promising and at the same time rapidly growinghealthcare areas is the wearable devices that assist individuals keepingtrack of their everyday activities. Preventive medicine and real timemonitoring services are gaining an increasing emphasis driven by theincreasing need for chronic disease management, patient empowerment,wellness and aging population support.

To date, there is a plurality of applications and services supported bymodern smartphones and mobile applications using embedded or externalsensing devices for capturing e.g. physical activity, fitness and sleeppatterns, etc.

However, most of known devices are highly inaccurate, not standardized,and not considered as medical grade devices, but rather as fitnesstrackers. That is, there is no known wearable device achieving highlyaccurate readings of vital signs such as blood oxygen levels.

In addition, known devices may comprise limited functionalities and/ormay be aesthetically not appealing to users for continuous or everydayuse.

In conclusion, there is a need for providing wearable devices, systemsand/or methods that provide a medical grade accuracy of a complete setof vital signs via non-invasive measurements without compromisingcomfort or aesthetic appeal.

SUMMARY

In a first aspect, wrist-watch back case for replacing a removable backcase of a timekeeping device or to be attached thereto, is provided. Thewrist-watch back case comprises a casing comprising a bottom wall and aside thereby defining an inner empty space and having at least fiveopenings at the bottom wall. The back case also comprises anoptoelectronic circuit board to be fitted in the inner space of thecasing. The optoelectronic circuit board comprises at least two pairedradiation sources to impinge radiation on user skin when the wrist-watchis worn by the user. Each source has a different emission wave lengthand at least one radiation detector to detect the reflected radiationexiting from skin and to transform it into a processable signal. Theradiation sources and radiation detector are arranged in correspondenceto the at least five openings.

A claimed casing enables transforming a timekeeping wristband deviceinto a smart medical apparatus, capable of accurately measuring aplurality of health-related biomarkers without altering thefunctionality and/or the characteristics of the timekeeping device. Theneed of an extra display may also be avoided.

In addition, the back case enables a user to choose between replacingthe replaceable back case or attaching the proposed back case to anexisting back case thereby the apparatus is easy to use.

The claimed back case is simple and cost effective as the user does notneed to buy a completely new device as the proposed back case permitsusing the user's own timekeeping device. As a result, the aestheticdesign is neither altered nor compromised as the back case can also beattached to a timekeeping device (watch).

In addition, the use of a claimed back case ensures an optimalsensor-body contact with the radiation sources.

In some examples, the back case may further comprise radiation guidingelements.

In some examples, the back case may further comprise a temperaturesensor for measuring user body temperature.

In some examples, the back case may further comprise fastening elementsto attach the back case to a timekeeping device.

In some examples, the back case may further comprise a first thermallyinsulating layer to thermally insulate back casing.

In some examples, the radiation detector is a photodiode.

In some examples, the radiation detector may further comprise filters,e.g. optical filters. A photoplethysmogram (PPG) signal may begenerated. A photoplethysmogram (PPG) is an optically obtainedabsorption signal. It may be acquired by using a radiation source whichilluminates the skin and a radiation detector to measure changes inlight absorption reflecting the volumetric variations of bloodcirculation.

In another aspect, a method for non-invasive measurements of biomarkersis provided. The method comprises providing at least two pairedradiation sources having different wave lengths, illuminating the skinwith the at least two radiation sources and capturing the radiationexiting from the skin. The method further comprises generating anabsorption (PPG) signal, extracting the epochs from the PPG signal;identifying the pulses on the PPG signal and filtering the PPG signal.The filtering step is repeated for all pulses until each pulse is withina predetermined reliability range.

By using such a method an increased accuracy of biomarkers is providedand so medical grade measurements may therefore be obtained.

In some examples, the method may further comprise illuminating the skinwith a predefined wavelength until the maximum gain is reached.

In some examples, the method may further comprise calculating anacceptable (artefact-free) derived PPG signal (PPGd).

In some examples, filtering the PPG signal comprises rejecting non-idealpulses.

In some examples, the method may further comprise extracting featuresfrom the PPGd signal. A PPGd signal having a plurality of epochscomprising pulses may be provided and the pulses of each epoch of thePPGd signal may be separated.

In some examples, the method may further comprise outputting a featureset for calculating biomarkers.

In another aspect, a method for calculating blood oxygen level (SpO₂) isprovided. The method comprises providing a PPGd signal, separating thePPGd signal into pulse waves and calculating the absorption/emissionpeaks. The method also comprises calculating RatioR from theabsorption/emission peaks, calculating extinction coefficients ofoxyhemoglobin and deoxyhemoglobin, and calculating unique wavepropagation calibration coefficient (a).

In another aspect a method for calculating blood pressure (BP) isprovided. The method comprises ensuring an ideal noise free environment,contacting the skin with a device according to aspects disclosed hereinand estimating BP. Then BP is compared with a predetermined range, andthe user is suggested to measure BP with conventional sphygmomanometerwhen the BP is out of the predetermined range.

In another aspect a system for non-invasive measurements of biomarkersis provided. The system comprises an illumination module comprising atleast two paired radiation sources, a capture module comprising at leastone radiation detector and a calculation module for calculating anabsorption signal. The system also comprises a feature extraction modulefor extracting features from the absorption signal and a communicationmodule for managing the communications between the calculation andfeature extraction modules.

In another aspect a watchband to be attached around a wrist of a user inan adjustable manner for non-invasive measurements of biomarkers isprovided. The watchband comprises a textile layer having perforations toadapt the degree of fixation, coupling elements for coupling thewatchband to a watch face and a buckle coupled to an end of thewristband. The buckle has a frame and a pivoting prong coupled to theframe. The watchband also comprises a tightening mechanism for obtaininga predefined fixation on the wrist. The tightening mechanism comprises aratchet gear having locking teeth in a predetermined angular range and apivoting strut to engage the ratchet gear. The tightening mechanism maybe arranged at a side of the buckle of a wristband or one tighteningmechanism may be arranged at each side for better stability.

A tighten fixation and thus, an optimized sensor-body contact is therebyfacilitated which improves and assures the accuracy of the measurementsi.e. of the calculated biomarkers.

In another aspect a timekeeping device is provided. The timekeepingdevice comprises a wristband according to aspects disclosedhereinbefore, and a back case according to aspects disclosedhereinbefore.

In another aspect system for non-invasive measurements of biomarkers isprovided. The system comprises a back case according to aspectsdisclosed hereinbefore, an interface module, and a mobile device forcontrolling signal acquisition procedure, acquisition mode andacquisition parameters as well as processing all the signals andperforming the calculation methods as disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting examples of the present disclosure will be described in thefollowing, with reference to the appended drawings, in which:

FIG. 1 schematically illustrates a back case according to an example;

FIG. 2 schematically illustrates a back case according to an example;

FIG. 3 schematically illustrates an optoelectronic circuit boardaccording to an example;

FIG. 4 schematically illustrates a watchband according to an example;

FIG. 5 schematically illustrates a tightening mechanism according to anexample;

FIG. 6 schematically illustrates a system according to an example;

FIG. 7 schematically illustrates a system according to an example;

FIG. 8A schematically illustrates a flow chart of a method according toan example;

FIG. 8B schematically illustrates a flow chart of a method according toan example;

FIG. 9 schematically illustrates a flow chart of a method for extractingfeatures according to an example;

FIG. 10 schematically illustrates a flow chart of a method forcalculating biomarkers according to an example;

FIG. 11 schematically illustrates a flow chart of a method forcalculating blood pressure according to an example; and

FIG. 12 schematically illustrates a flow chart of a method forcalculating blood oxygen level according to an example.

DETAILED DESCRIPTION

FIG. 1 shows a back case 100 to be attached to an existing back case ofa timekeeping device. The back case 100 may comprise a bottom wall 102and a side wall 101 surrounding the bottom wall thereby forming an innerempty space for fitting an electronics circuit board (later ondisclosed).

The back case 100 may be made of e.g. plastic, metal, carbon fiber orany other suitable material.

The bottom wall 102 may comprise openings 103, 104 for receiving anelement of a circuit board and openings 105 for attaching the circuitboard to the bottom wall 102.

The bottom wall may comprise a central opening, a pair of openingssurrounding the central opening and openings near the periphery of thebottom wall.

In an example, the bottom wall 102 may comprise openings 103 forreceiving radiation sources, an opening 104 for receiving a radiationdetector and other elements e.g. a temperature sensor and openings 105for fastening the electronics circuit board to the bottom wall. Thediameter of each opening 103-105 may vary depending on the element to bereceived therein. For instance, openings 103 for receiving radiationsources may comprise a diameter smaller than the diameter of opening 104for receiving a radiation detector.

In an example, the back case 100 may comprise an opening 104 forreceiving a radiation detector arranged in the bottom wall 102 and fourradiation source openings 103 arranged around and in the proximity ofthe opening 105 for receiving the detector. The four radiation sourceopenings 103 may be arranged at 90 degrees with respect to each otherand. A pair of such opposite, i.e. arranged at 180 degrees with respectto each other, radiator source openings 103 may be situated at a closerdistance to the opening 104 than the other opposing radiator openingsources.

The bottom wall 102 may comprise any shape e.g. substantially rounded,elliptical, etc., for adapting to the watch face of a certaintimekeeping device and therefore avoid part of the back case 100 fromprotruding out of the timekeeping face which may be uncomfortable andmay even cause injuries to the user. In an example, the bottom wall 102may be substantially circular and its diameter, i.e. the diameter of theback case 100, may be of about 30-50 mm. In an example, the diameter maybe 38 mm. In another example, the diameter may be about 42 mm.

The back case 100 may, after inserting a circuit board therein, beattached to an existing back case of a timekeeping device by an adhesiveprovided on the surface of the side wall or by any other suitablemethod.

In some examples, the back case 100 may replace the existing back caseof a timekeeping device.

FIG. 2 depicts an example of a back case 200 which differs from the backcase 100 of FIG. 1 in that the side wall 201 may comprise fasteningelements, e.g. laterally protruding flaps 206 to fasten the back case tothe timekeeping device. In an example, the fastening elements maycomprise screws (not shown) to provide a secure fastening of the backcase to the timekeeping device.

In addition, the height of the side wall 201 may be different than thatin the example of FIG. 1, thereby forming a deeper or shallower innerspace.

The back case 100, 200 according to any of the disclosed examples mayfurther comprise a first insulating layer (not shown) to insulate theinner space. In an example, the first insulating layer may be thermallyinsulating layer and/or a moisture insulating layer. The firstinsulating layer may be arranged at the sidewall, i.e. at the peripheryof the back casing, thereby thermally and/or hermetically sealing theinner space there between when coupling the back case to a timekeepingdevice. A thermally conductive ring may be in contact with the skin andconduct the heat to the sensor, which is inside the casing. In anexample, the conductive ring may be made of metal.

FIG. 3 depicts a circuit board 300, e.g. an optoelectronic circuitboard, to be fitted within a back case 100, 200 according to any of thedisclosed examples. The optoelectronic circuit board 300 may comprise abase plate 301 e.g. a printed circuit board (PCB), in which differentelectronic and/or optoelectronic elements may be arranged. Theoptoelectronic circuit board 300 may have a shape corresponding to theshape of the bottom wall 102, 202 of a back case 100, 200 to be easilyfitted therein.

The optoelectronic circuit board 300 may comprise at least two pairedradiation sources 303A, 303B for generating emissions having twodifferent wavelengths e.g. visible, near infrared (NIR), infrared (IR)or any combination thereof, thereby obtaining a different penetrationdegree into the skin.

The first paired radiation sources 303A may emit radiation of a firstwavelength λ1 that may achieve a deeper skin penetration, i.e. may reachlarge arteries. Such first wavelength λ1 may be less sensitive tooxyhemoglobin content thereby yielding a more stable signal over thetime and less dependent on temperature. The second paired radiationsources 303B may emit radiation of a second wavelength λ2. Suchradiation may penetrate less in the tissues but may capture largeintensity variations, i.e. may comprise greater absorptivity.

The at least two paired radiation sources 303A, 303B may emit radiationsubsequently, i.e. the emission may not be simultaneous.

The paired radiation sources 303A, 303B may impinge the body in apulsed, continuous, frequency modulated, amplitude modulated,polarization or phase modulated mode in order to detect the intrinsiccomponents of the tissue. In an example, the radiation sources 303A,303B may be LED emitters or laser diodes.

The optoelectronic circuit board 300 may also comprise at least aradiation detector 304 e.g. a photodiode, to detect the light exitingfrom the body. The radiation source may also be provided with filters,i.e., dielectric coatings, diffractive elements or any type ofwavelength selection element (not shown) and may generate aphotoplethysmogram (PPG) signal.

The optoelectronic circuit board 300 may comprise a first set ofradiation guiding elements (not shown) to be arranged between theradiation detector 304 and patient skin for providing a coupling of theradiation exiting from the user skin and thereby improve the accuracyand reliability of measurements. The optoelectronic circuit board 300may comprise a second set of radiation guiding elements (not shown) tobe arranged between each of the paired radiation sources 303A and 303Band user skin for providing an optimum coupling of the radiationentering the user skin and thereby improve the accuracy and reliabilityof measurements. The guiding elements may be microlenses, Fresnellenses, diffraction elements, optical fibers, waveguides, photonicstructures, etc.

The optoelectronic circuit board 300 may also comprise a power modulecomprising rechargeable battery 302 e.g. a lithium-ion polymer battery,and a battery charging element 306 which may charge the battery throughwireless electromagnetic induction. The battery charging element 306e.g. a charging coil, may be arranged on the periphery, i.e. around, theoptoelectronic circuit board 300. Such power module may further compriseat least two voltage regulators to stabilize voltages of all electronicand optoelectronic components.

The optoelectronic circuit board 300 may comprise an analog to digitalfront end (AFE) 307, e.g. a system on chip (SoC). The AFE 307 maycomprise an analog to digital converter (ADC) which may transform thedetected exiting radiation analogic signal of the radiator detector intoa digital signal e.g. of 22 bits. The AFE 307 may further controltimings, sampling and radiation intensity parameters of the dataacquisition, i.e. of the radiation entering and exiting the user body.

In some examples, the AFE 307 may not drive more than two differentpaired radiation sources (emitters) simultaneously, therefore the AFE307 may comprise a selection circuit (not shown) for selecting pairedradiation sources to impinge radiation on user skin. The selected pairedradiation sources may emit radiation having Visible wavelength only,Near Infrared (NIR) wavelength only, Infrared (IR) wavelength only,Visible and NIR wavelength interchanged, NIR and IR wavelengthinterchanged, and Visible and IR wavelength interchanged.

In an example, there may be as many selection circuits as radiationsource pairs.

In addition, the optoelectronic circuit board 300 may comprise atemperature and inertial measurement unit (TIMU) 305, e.g. a low powerintegrated microelectromechanical system (MEMS).

The TIMU 305 may comprise a temperature sensor and also an inertialmeasurement unit, e.g. an inertial sensor, which may comprise aplurality of magnetic field channels and a plurality of accelerationchannels, each having adjustable scales. The measured signals of bothmagnetic field and acceleration channels may be used e.g. as artefactrejection, PPG signal quality assessment, etc.

In an example, the adjustable scales may be ±2, ±4, ±8 and ±12 gaussmagnetic full scale, and ±2, ±4, ±6, ±8 or ±16 linear acceleration fullscale.

In an example, the TIMU may comprise 3 magnetic field channels and 3acceleration channels.

The inertial sensor of the TIMU 305 may measure the acceleration of theoptoelectronic board and thus of the back case.

The temperature sensor may comprise a second thermally insulating layer(not shown) arranged for thermally decoupling the temperature sensorfrom remaining electronic components of the optoelectronic circuit board300. By thermally decoupling the temperature sensor and together withthe first thermally insulating layer, arranged between the back case anda timekeeping device the temperature measurement accuracy is improved. Athermally conductive ring is in contact with the skin and conducts theheat to the sensor, which is inside the casing.

The optoelectronic circuit board 300 may further comprise a control andcommunication module (MCUBT) 309, e.g. a system on chip (SoC), which maycommunicate with the AFE and the TIMU to enable a fast data acquisitioni.e. at sampling rates of at least 500 Hz for the AFE and at least 100Hz for the TIMU. The control and communication module 309 may furthercommunicate with an external (mobile) device, e.g. a smartphone, atablet, a computer, etc., to provide the acquired data. Such an externaldevice may control the signal processing and the measuring process. Insome example, an external device may also control the selection circuitof the AFE.

The control and communication module 309 may comprise a microprocessorand a communication module, e.g. Bluetooth.

In an example, the optoelectronic circuit board 300 may further compriseoptoacoustic emitters and receivers (not shown). The acoustic emittersand radiation sources may be multiplexed.

In an example, the optoelectronic circuit board 300 may further comprisean interface module (not shown). The optoelectronic board may comprise acontrol module for initiating and controlling the data acquisitionparameters, a communication module for managing the communications withan external mobile device and two voltage regulators. The optoelectronicboard may additionally comprise an analogue to digital front end formanaging the conversion of the analogue signal received by the radiationdetector to a digital one, and for controlling the radiation sources.

In an example, the optoelectronic circuit board 300 may be fixed to thebottom wall 102, 202 of the back case 100, 200 by adhesive, by couplingelements or any other suitable method.

Once the optoelectronic circuit board 300 is assembled within the innerspace of the housing of a back case 100, 200 according to any of thedisclosed examples, the resulting back case may be ready to be attachedto or to replace an existing back case of a wrist watch or othertimekeeping device. When the proposed back case is to be attached to anexisting back case a thin cover may be placed between the case and thewatch body for protection, e.g. against moisture accumulation.

The assembled back case, i.e. the back case having the optoelectroniccircuit board within the housing, may have a thickness determined by thethickness of the height of the side wall. In an example, the battery mayhave a thickness of about 1.9 mm, the charging coil may have a thicknessof about 0.4 mm and the side wall a height of about 0.8-2 mm.

In an example, the optoelectronic circuit board 300 may comprise morethan two paired radiation sources e.g. near infrared, short waveinfrared, infrared, mid-infrared, etc. for measuring tissue constituentssuch as water, lipids e.g. yellow and brown fat, and glucose. Additionaland related biomarkers, e.g. hydration, lipid metabolic activity, bloodsugar levels and glucose metabolic activity, may also be thencalculated.

The back case and the optoelectronic circuit board may be manufacturede.g. by CNC machining, milling, moulding, press fitting, 3D printing,etc. Any suitable material such as metal e.g. stainless steel, titanium,aluminium, gold, silver; plastic, composite materials, carbon fibre orany combination may be used to manufacture a back case and/or anoptoelectronic circuit board according to any of the disclosed examples.

FIG. 4 depicts the bottom view of a watchband or a timekeeping band 400to be attached around a user wrist in an adjustable manner. Thewatchband 400 may comprise a flexible layer 401 e.g. made of fabric,plastic, leather, metal, etc., that may have a first 410 and a secondportions 420 to be coupled to the watch body 1 of a timekeeping device.The watchband 400 may further comprise coupling elements 402 forcoupling the watch face 1 to the flexible layer 401.

The first portion 410 may comprise adjusting elements 411, e.g.perforations, in order to enable the user to adapt the watchband to thesize of user wrist. The second portion 420 may comprise a buckle 440arranged at an end 421 of the flexible layer. The buckle 440 maycomprise a frame 441 and a pivoting prong 442 coupled to the frame. Thepivoting prong 442 may be introduced in a specific adjusting element toadjust the watchband to the user wrist.

In order to ensure a proper counterforce when fastening the watchband400 i.e. when pulling up the buckle, around the wrist of the user, thewatchband may further comprise a solid plate 430 e.g. made of metal,which may be arranged below the flexible layer.

The watchband 400 may replace the existing fastening system of atimekeeping device thereby ensuring a tighten fixation which aids tomaintain the sensor-body contact pressure and improves the signal whileavoiding vasoconstriction and/or user discomfort.

Additionally, the watchband 400 may further comprise a tighteningmechanism 500 that may be arranged in the frame of the buckle 440. Theuse of the tightening mechanism 500 enables obtaining a predefinedfixation on the wrist and thereby improving the sensor-skin contact andthe accuracy of measurements.

FIG. 5 shows a tightening mechanism 500 that may be arranged at a sideof the buckle. The tightening mechanism 500 may comprise a ratchet gear510 having a plurality of locking teeth arranged at the periphery, overa predetermined angular range and facing a pivoting strut 520 that mayengage the teeth. The mechanism 500 may further comprise an unlockingmechanism 530, e.g. a knob, and compression spring (not shown) forholding the unlocking mechanism 530 against the pivoting strut againstthe ratchet gear 510.

In order to unlock the mechanism, the user may press the unlockingmechanism and release the pivoting strut.

The buckle can freely move in the opposite direction to locking therebyallowing the watch band to form a circular shape around the wrist whenno measurement is taken.

In an example, the watchband 400 may comprise two tightening mechanisms500 arranged at opposite sides of the buckle.

FIG. 6 depicts a system 600 which may comprise an illumination module601 comprising at least two paired radiation sources according to any ofthe disclosed examples for illuminating user skin, a capture module 602comprising at least one radiation detector for detecting the lightexiting from the user according to any of the disclosed examples and acalculation module 603 for calculating an absorption signal. The system600 may further comprise a feature extraction module 604 for extractingfeatures from the absorption signal and a communication module 605 formanaging the communications between the calculation and featureextraction modules. In an example, the communication module may furthermanage communications between the system 600 and an externalcommunication device 610.

FIG. 7 depicts a system 700 for non-invasive measurements of biomarkerswhich may comprise a back case 701 according to any of the disclosedexamples and wherein the back case may comprise an optoelectroniccircuit board 702 according to any of the disclosed examples. The system700 may comprise an interface module 703 and a mobile device 704 forcontrolling signal acquisition procedure, acquisition mode andacquisition parameters. In an example, the system 700 may furthercomprise a detachable device for obtaining measurements in a differentbody position. The detachable device may be adhered to user body e.g. ina removable manner. In an example, the detachable device may be asticker.

FIG. 8A depicts a block diagram of a method 800 for non-invasivemeasurements of biomarkers which may be implemented with a back casecomprising an optoelectronic circuit according to any of the disclosedexamples. Firstly, the at least two paired radiation sources havingdifferent wave lengths λ1, λ2 may be provided.

In an example, the first wave length λ1 may achieve deeper penetrationthan the second wave length λ2 which may only achieve superficialpenetration. The first wave length λ1 may be, e.g. red light, infrared(IR) or near infrared (NIR), and when comparing with second wave lengthλ2, it may be less sensitive to oxyhemoglobin and therefore more stableover time, and less sensitive to temperature. The second wave length λ2,e.g. green light, may capture large intensity variations as it may havegreater absorption of oxyhemoglobin and deoxyhemoglobin and so thecardiac cycle may be better reflected. By using such different wavelengths a better signal to noise ratio (SNR) may therefore be achieved.In addition, the second wave length λ2 may be more sensitive totemperature and vasodilatation/constriction.

Once a back case is attached or coupled to a timekeeping device and thelatter fastened e.g. around user wrist, the user skin may beilluminated, in block 801, with at least two paired radiation sourceshaving different wave lengths. The acquired signal and the skinpenetration may therefore be improved. In an example, the skin may beinterchangeably illuminated by the two paired radiation sources. In anexample, the skin may be firstly illuminated by an IR or NIR radiationwave length to get robust PPG signal in reflectance mode.

Then, in block 802, the radiation exiting from the skin, i.e. thereflected radiation, may be captured, e.g. by a radiation detectorarranged on the optoelectronic circuit board of the back case, and anabsorption signal, e.g. a PPG signal, may be generated, in block 803, bythe radiation detector. Then, in block 804, the signal epochs or epochsof the PPG signal may be extracted. Signal epochs are signal segments orsignal frame lengths of a predefined length which may be long enough tofacilitate robust statistical information and short enough to capturenon-stationary information. In an example, the length of each epoch maybe of about 8 seconds to accommodate 8-10 heart cycles within.

Pulses and/or pulse morphology of the PPG signal may then, in block 805,be identified and the PPG signal may then be filtered, in block 806, toget ideal artefact free PPG signal. In an example, the filtering maycomprise rejecting whole pulses.

The filtering may then be repeated for all pulses of every signal epochuntil each signal epoch is within a predetermined reliability range.

Then, in block 807, filtered pulsed, i.e. non-removed pulses, may becollated thereby forming an acceptable (artefact free or ideal) derivedPPG signal. The derived PPG signal (PPGd) may then be used forcalculating the biomarkers (later on disclosed).

In an example, the method 800 may further comprise assessing SNR_(PPG)of the PPG signal to verify whether SNR_(PPG) is within an acceptablerange of values. The SNR_(PPG) of the PPG signal may indicate the levelof the clinically useful signal to the level of background noise. In anexample, the SNR_(PPG) may be the ratio of filtered PPG signal varianceto the unfiltered raw signal, i.e. noise, variance.

In an example, the method may further comprise assessing the PPG signalquality which may be performed e.g. by Kurtosis, Skewness or any othersuitable method. The Skewness (S_(PPG)) is defined as:

$S_{PPG} = \frac{E\left( {x - \mu_{x}} \right)}{\sigma_{x}^{3}}$

where x is the raw, i.e. unfiltered, PPG signal, μ_(x) and σ_(x) are theempirical estimates of the mean and standard deviation of x, and E isthe expected value operator.

In an alternative example, Perfusion index (PI_(PPG)) of the PPG signalmay be used to calculate PPG signal quality. The PI_(PPG) is the ratioof the pulsatile blood flow (AC) to the non-pulsatile or static blood inperipheral tissue (DC), and represents the represents the difference ofthe amount of light absorbed through the pulse of when light istransmitted through the tissue. The PI_(PPG) may be calculated as:

${PI}_{PPG} = {{\frac{AC}{DC} \times 100} = {\frac{\left( {{{emmission}\mspace{14mu} {peak}} - {{absortion}\mspace{14mu} {peak}}} \right)}{\mu_{x}} \times 100}}$

Wherein μ_(x) is the raw unfiltered signal mean, and emission andabsorption peaks are calculated on the filtered signal.

In case the SNR is out of the predefined range of values, the skin maybe further illuminated with a predefined wave length radiation e.g.916-960 nm, IR/NIR wavelength, until the maximum possible gain limits ofthe illumination driver is reached. The SNR_(PPG), PI_(PPG) or S_(PPG)may then be re-evaluated and, in the event that a non-working signalpersists and no further gain increase may be achieved, the skin may beilluminated by alternative radiation having a wave length of e.g.510-522 nm, corresponding to green colour wavelength. The amplificationgain can be also increased in order to ensure better SNR.

In an example, temperature may also be closely monitored, since coldtemperature conditions may significantly reduce PPG signal quality,whereas warm temperature conditions may improve the quality of the PPGsignal e.g. up to four times. Warm temperature conditions ensurereliable measurements related to peripheral extraction and circulation.

FIG. 8B schematically illustrates a detailed implementation of themethod of FIG. 8A. In block 8010 the method may be initiated when acondition is met (e.g. user selection, a predetermined time interval isreached, a time of the day etc.). In block 8020 the skin may beilluminated using e.g. IR/NIR wavelengths. In block 8040 a PPG signalmay be captured and epochs may be extracted. The SNR may be assessedbased on the absorption properties of the skin and the tightness of thestrap around the wrist of the user. In decision box 8042, it may bedetermined if the SNR assessed is acceptable. If the SNR is determinedto be not acceptable then in decision box 8044 it may be determined ifthe gain or frequency of the signal may be increased. If the gain can beincreased, then in block 8060 the amplifier gain is increased and themethod moves back to block 8040. If in decision box 8044 it isdetermined that the gain or frequency cannot be further increased, thenthe skin may be illuminated using a green wavelength in box 8080 and theprocess moves back to box 8040. Now, if after the aforementionedfeedback control loop involving optimizing timing, intensity, gain orswitching wavelength, the SNR is determined to be acceptable in decisionbox 8042. Then in box 8100 the distinct pulses' morphology may beidentified to meet a predefined PPG signal template considered as ideal.By using a plurality of template matching algorithms, such as the CommonSpatial Patterns (CSP) technique, template subtraction,Principal/Independent Component Analysis (PCA/ICA), simple Correlationor alternative, that may compare the actual signal with the templatesignal a similarity may be identified. A dynamic time warping may beused to stretch each beat to match the ideal running template. Thisprocess may be repeated for every pulse in each signal epoch until anideal PPG derived signal (PPGd) is captured in box 8140. The process maythen end in box 8150. As mentioned, the epoch is defined as the signalframe length able to accommodate about 8 to 10 heart cycles, long enoughto capture robust statistical signal information, yet short enough tocapture nonstationary information. Decision box 8105 may determine ifpulse is acceptable and in box 8120 suboptimal pulses may be rejected.

FIG. 9 depicts a block diagram of a method 900 for extracting a featureoutput set which may be used to calculate biomarkers. Biomarkers mayinclude Heart Rate (HR), Heart Rate Variability (HRV), Blood OxygenLevel (SpO₂), Cardiac Output (CO), Blood Pressure (BP), Respiratory Rate(RR), Arterial Stiffness (AS), Blood Flow Volume (BFV), Temperature andActivity tracking, etc.

Firstly, a PPGd signal e.g. the signal calculated from method 800,comprising a plurality of epochs having pulses may be provided, in block901. The pulses of the PPGd signal may, in block 908, be separated.

In addition, the falling edge ePW(i) of each pulse (i denotes eachpulse) may be extracted, in block 910, and the beginning and end tailsof each ePW(i) may be discarded, in block 912, to eliminate edgediscrepancies. To that end an empirically defined threshold value, e.g.equal to a length segment of 0.2*HR seconds, may be used.

The first derivative of each ePW(i) may then be calculated, in block914, and filtered, in block 916, e.g. by low pass filter, in order tosmooth out high frequency content. In an example, a moving averagefiltering with windows size of 31 samples may be used for filtering thefirst derivative.

The filtered first derivative may then be used to find the zerocrossings (zCx), in block 920, e.g. using a step by step zero-crossingadaptive/non-adaptive technique.

In the event the zero crossings are found, their location may bedetermined and a respective ePW(i) dicrotic notch/incisura position maybe found and assigned, in block 924, and such value stored in a memorydevice. The algorithm may be moved to the subsequent pulse, in block926. The process may be repeated for all the pulses of the PPGd signal.We use the terms dicrotic notch and incisura to refer descriptively tothe two possible positions of the notch. In the first case, (if theposition is matched with an upstroke) we name it to be a “dicroticnotch”, whether in the latter case, (if the position matches aninflection of the waveform) we will refer to it as an incisura.

On the contrary, in the event the zero crossings are not found, thepeaks of first derivative of ePW(i) may be found, in block 918, and maybe used to analyse each peak position in a descending order thereby tolocating the peak corresponding to the incisura peak, in block 922. Inan example, the selection of the peak may be based on position criteriawith respect to the inter-beat time.

The output of block 922, may then be evaluated and used to determine theincisura position if it fulfils certain inclusion criteria, as follows:Disjoint pulses (908) are identified to be: upstrokes (upslope), ordownstrokes (downslope) and inflections—based on the bending pattern ofthe pulse under study. The “dicrotic notch and/or incisura peak” isidentified if one or more of the following criteria are met: adownstroke followed by a small upstroke and/or a downstroke followed byan inflection and an upstroke and/or a downstroke followed by aninflection and another downstroke. If more than one of these isidentified, we select the one with the higher slope (negative/positive)curvature in the respected segment of question.

The algorithm may be moved to the subsequent pulse, in block 926.

In parallel to the separation of the pulses of the PPGd signal, theemission and absorption peaks of the PPGd signal may similarly bedetected, in blocks 904 and 906, respectively, e.g. by using analgorithm based on geometric definition of signal trends and thestatistical definition of peaks and valleys.

Additionally, the method 900 may further comprise calculating the secondderivative of the PPGd signal, in block 914 a, after separating thepulses of the PPGd signal. Then, the maximum and minimum peaks of thesecond derivative of the PPGd signal may be found, in block 916 a, andthe ratio of the maximum peak to the minimum peak may be calculated.

After processing all PPGd's pulses, all epoch's dicrotic notch/incisuramay be retrieved, in block 928, and a feature output set may becalculated, in block 930, by adding the emission and absorption peakslatency and amplitude, the peak and valley latency of the PPGd's secondderivative, as well as the computed epoch's HR (902) that may becalculated using e.g. dominant frequency extraction techniques or timedomain detection techniques (i.e. autocorrelation).

The output feature set (f1-f8) may comprise: Pulse Transit Time (PTT),defined by the difference in latency within each pulse between thedicrotic notch and the absorption peak of the same pulse (f1),Amplitude/Latency of emission peak (f2), Amplitude/Latency of absorptionpeak (f3), Amplitude/Latency of dicrotic notch/incisura peak (f4), HeartRate (HR) (f5), Time span between Maximum peak of first derivative anddicrotic notch/incisura peak of PPGd pulse (f6), the second derivativetime span between maximum and minimum peak (f7) and PPGdIR ratio of PPGdepoch emission and absorption peak amplitude (f8).

In an example, the output features may then be used to compute thebiomarkers for instance by method 1000 (later on disclosed).

FIG. 10 depicts a block diagram of method 1000 for calculatingbiomarkers, which may be subsequent to method 900 of FIG. 9. Firstly,the features may be extracted from the PPGd signal, in block 1001, and,in block 1002, the extracted features may be compared with previouslystored features. In the event of statistically significant non-matchingfeatures, such features may be rejected.

The biomarkers may then be calculated, in block 1004, and calculatedbiomarkers may be compared, in block 1006, with values of previousmeasures e.g. of previous day, week, month, etc., in search orvariability patterns i.e. capture at same time and similar activitylevel.

FIG. 11 depicts a method 1100 for calculating Blood Pressure (BP) whichmay accurately estimate the BP using an output feature set f1-f8calculated according to any of the disclosed examples. Firstly, an idealnoise free environment may be secured, in block 1101.

To get a noise free environment and improve the measurements, the usermay be in a resting position, e.g. sitting upright on a chair. The usermay use a system for non-invasive measurements according to any of thedisclosed examples, i.e. comprising at least a back case, an interfacemodule and a mobile device, attached thereto. In an example, the devicemay be leveled with the user heart and the feet flat on the floor.

In order to avoid obstructing blood flow, the excess of clothing oranything that could possibly block unobstructed blood flow in the armmay be removed. As a precautionary measure, reading or talking whiletaking measurements should be avoided for ensuring proper measurements.Before taking the first measurement, the user may tighten the watchband,in block 1102, e.g. via a tightening mechanism according to any of thedisclosed examples, and thereby ensure a firm contact to the skinwithout risking overtightening. A first measurement may then be taken,after e.g. 5 minutes to allow for the individual to relax and the BP maythen be estimated, in block 1104.

Blood Pressure (BP) is related to multiple factors such as bloodhemodynamics, blood density and arterial physical properties i.e.thickness, diameter, and elasticity, stroke volume, heart rate, cardiacoutput, peripheral resistance, circulating blood volume, blood vessels,nervous system, circulatory system, respiration, emotion and otheranthropic factors.

In an example, the method 1100 for calculating BP i.e. both systolic(SBP) and diastolic (DBP) blood pressures, relates to the features f1-f8which may be closely selected to match different physiologicalproperties of the cardiovascular system under study e.g. for reflectingperipheral resistance, vessel elasticity, cardiac output, blood volumeand contribute to both the SBP and DBP calculation. Contrary to knownPPT-based models, method 1100 is heavily depended on the dicrotic notchidentification that carries significant physiological information. Inmethod 1100 a particular attention may be paid on getting optimal signalquality from the wrist. All measurements and calculations may beperformed by using a noise free, high quality PPGd signal.

The output features f1-f8 may be subjected to both linear and nonlinearmultivariate analysis to build a BP estimation model.

In an example, Mean Square Error (MSE) loss function of eitherMulti-Layer Perceptron (MLP) or Regression Forests (RF), may be used toperform machine learning. Thereby an improved performance over time maybe achieved, as compared to the faster Multivariate Linear Regressionmethod (GLR).

In another example, ensemble learning may be used, that is, MLP, RF andGLR may be combined in order to improve the confidence of the BPestimation using majority voting. All BP models may be trained, i.e.calibrated, to output the widely used mmHg sphygmomanometer scale.

In another example, the user height, age, gender and health status mayalso be taken into account to derive BP measurements in each PPGd epoch.

For the training and validation phase, a static BP estimation experimenton 50 healthy normotensive adults (25 men and 25 women) with an agerange 26-44 may be used. Assuming that the user was not exercising justbefore taking the measurement, the activity state may automatically beextracted from the TIMU sensor of the device, in block 604, BPestimation may be evaluated and in the event that BP moves outside ofthe bounds of normalcy, the user may be advised, in block 1108, to getan additional measurement with conventional sphygmomanometer.

In such a case, the values of three successive sphygmomanometermeasurements, e.g. taken with an interval of 1 minute, may then enterede.g. manually, into a user interface, e.g. via a mobile app. In anexample, the system may be retrained i.e. recalibrated, to take accountfor the manually entered measurements and the difference with respect toestimated BP values, in block 1110.

The estimation error is found to increase one day after model training,with no further significant increase, afterwards. A bit shifted(erroneous) blood pressure value may be provided the first day afterinitial calibration. Hence, the user may be prompted to recalibrate thesystem after one day in order to properly account for possible BPprediction power loss.

In the event the method is used while exercising, the system may becapable of evaluating BP in the recovery phase to estimate, in block1106, the hypertension tendency of the user. In an example, the recoveryphase, blood pressure may be hypertensive if a value of 140/90 mm Hg isexceeded in the fifth minute.

FIG. 12 depicts a block diagram 1200 of a method for calculating thetissue Blood Oxygen Level (SpO2) from PPG readings.

The PPGd signal may be used as the basis for extracting meaningfulmeasures. The emission (f2) and absorption (f3) peaks may be detected asdescribed before in blocks 904 and 906, respectively. Then, in block1201, the PPGd signal calculated according to any of the disclosedexamples may be provided and the epochs of the PPGd may be segmented, inblock 1202, into disjoint pulse waves which may be used to calculate, inblock 1204, the latency, i.e. the amplitude, of emission and absorptionpeaks.

The user skin may, in an example, be illuminated with at least twodifferent wavelengths e.g. Green light and IR radiation. The use of theat least two different wavelengths penetrating and then exiting the usertissue enables obtaining different absorption with distinct extinctioncoefficients. Light extinction coefficients of blood components, i.e.oxyhemoglobin (HbO) and deoxyhemoglobin (Hb) may be calculated fromextinction coefficients as a function of wavelength measurements. Suchlight extinction coefficients are unique for each tissue impinging lightwavelength.

The method 1200 for calculating the tissue blood oxygen level (SpO2) mayfurther comprise calculating the RatioR, in block 1206, from theabsorption and emission peaks of the PPGd signal. RatioR may becalculated by:

${RatioR}{= \frac{\frac{{{emission}\mspace{14mu} {peak}\mspace{14mu} \left( {{wave}\; 1} \right)} - {{absorption}\mspace{14mu} {peak}\mspace{14mu} \left( {{wave}\mspace{14mu} 1} \right)}}{{absorption}\mspace{14mu} {peak}\mspace{14mu} \left( {{wave}\mspace{14mu} 1} \right)}}{\frac{{{emission}\mspace{14mu} {peak}\mspace{14mu} \left( {{wave}\; 2} \right)} - {{absorption}\mspace{14mu} {peak}\mspace{14mu} \left( {{wave}\mspace{14mu} 2} \right)}}{{absorption}\mspace{14mu} {peak}\mspace{14mu} \left( {{wave}\mspace{14mu} 2} \right)}}}$

Then, in block 1208, the extinction coefficients of oxyhemoglobin anddeoxyhemoglobin may i.e. HbO1, HbO2 and Hb1, Hb2, of impinging firstwavelength λ1 and second wavelength λ2, respectively, may be calculated.In an example, the first wavelength may correspond to green light andthe second wavelength may be IR.

In block 1210, the unique wave propagation calibration coefficient α maybe calculated according to predefined light propagation modelsaccounting for different absorption and scattering of first and secondwavelengths λ1, λ2 resulting to a difference of light propagation pathlength (L1, L2) within the illuminated tissue. Therefore, a may becalculated as:

$\alpha = \frac{L_{1}}{L_{2}}$

Then, in block 1212, the value of SpO₂ may be calculated by thefollowing formula:

${SpO}_{2} = {\frac{{Hb}_{1} - {{Hb}_{2}{aR}}}{{\left( {{HbO}_{2} - {Hb}_{2}} \right){aR}} + \left( {{HbO}_{1} - {Hb}_{1}} \right)} \times 100}$

In an alternative example, the Perfusion Index PI_(PPG) of each signalepoch may be used to calculate the RatioR for the two wavelengths bydividing PI_(PPG)(wave1)/PI_(PPG)(wave2).

However, a single measurement of a biomarker cannot allow a precisedetermination of user health status. In an example, the system accordingto any of the disclosed examples used to implement any of the disclosedmethods, may comprise a Personal Health Record (PHR) e.g. on the mobiledevice, thereby enabling short-term i.e. previous day, and/or long-term,i.e. previous week and month, comparative/contrasting vital signsmonitoring.

The Cardiac Output (CO) may be calculated as the reciprocal ratio of thesystolic and diastolic area of the PPGd pulse signals. The systolicarea, in a pulse, is defined as the area under the curve bounded by thebeginning of pulse and the dicrotic notch, whereas the diastolic area isbounded by the dicrotic notch and the end (absorption peak) of thepulse.

The Blood Flow Volume (BFV) is the volume of the blood measuredconsidering a specific PTT, physiological parameters of a human body,and measurement position, where according to one example the device maybe positioned on the posterior side of the wrist of a subject.

The Respiration Rate (RR) may be calculated using band pass filtering onFast Fourier Transform (FFT) peak detection over noisy quasi-periodicsignals selecting, according to one example, the dominant or mostimportant frequency prior to the cardiac frequency.

The Heart Rate Variability (HRV) may be calculated by jointly measuringthe interval time between emission, absorption and dicroticnotch/incisura peaks, according to one example the SD (standarddeviation) and RMSSD (root mean square of successive differences of beatto beat intervals in time domain).

The Arterial Stiffness (AS, ASI), an independent screening measure forcardiovascular risk, related to aging and elastic properties of thearteries shows the contribution of wave reflection to systolic arterialpressure, and according to one example may be approximated by the ratioof the maximum peak to the minimum peak of the second derivative.

Although only a number of examples have been disclosed herein, otheralternatives, modifications, uses and/or equivalents thereof arepossible. Furthermore, all possible combinations of the describedexamples are also covered. Thus, the scope of the present disclosureshould not be limited by particular examples, but should be determinedonly by a fair reading of the claims that follow. If reference signsrelated to drawings are placed in parentheses in a claim, they aresolely for attempting to increase the intelligibility of the claim, andshall not be construed as limiting the scope of the claim.

1. A wrist-watch back case to replace a removable back case of atimekeeping device or to be attached thereto, the wrist-watch back casecomprising: a casing comprising a bottom wall and a side wall therebydefining an inner empty space; at least five openings at the bottomwall, an optoelectronic circuit board to be fitted in the inner space ofthe casing, the board comprising, at least two paired radiation sourcesto impinge radiation on a user's skin when the wrist-watch is worn bythe user, each source having a different emission wave length to obtaina different degree of skin penetration, at least one radiation detectorto detect a reflected radiation signal exiting from the skin and totransform the reflected radiation signal into a processable signal,wherein the radiation sources and the radiation detector are arranged incorrespondence to the at least five openings.
 2. The wrist-watch backcase according to claim 1, further comprising radiation guiding elementsto provide a coupling of the reflected radiation
 3. The wrist-watch backcase according to claim 2, wherein the guiding elements are arrangedbetween a radiation detector or a radiation source and the user's skin.4.-20. (canceled)
 21. The wrist-watch back case according to claim 2,the optoelectronic board further comprising an interface modulecomprising: a control module for initiating and controlling the dataacquisition parameters, a communication module for managing thecommunications with an external mobile device, an analogue to digitalfront end for managing the conversion of the analogue signal received bythe radiation detector to a digital one and for controlling theradiation sources, and two voltage regulators.
 22. (canceled)
 23. Amethod for non-invasive measurements of biomarkers, comprising:providing at least two paired radiation sources having different wavelengths; illuminating a skin with the at least two radiation sources;capturing the radiation exiting from the skin; generating an absorption(PPG) signal; extracting the epochs from the PPG signal; identifying thepulses on the PPG signal; filtering the PPG signal by rejectingnon-acceptable pulses; and repeating the filtering step for all pulsesuntil each pulse is within a predetermined reliability range.
 24. Themethod according to claim 23, further comprising illuminating the skinwith a predefined wavelength until the maximum gain is reached.
 25. Themethod according to claim 24, wherein illuminating the skin with apredefined wavelength comprises illuminating at a wavelength of 916-960nm assessing a signal-to-noise ratio (SNR) and increasing theamplification gain of illuminating the skin.
 26. The method according toclaim 25, further comprising assessing a signal-to-noise ratio (SNR) andincreasing an amplification gain of illuminating the skin with apredefined wavelength of 510-522 nm if the SNR is out of a predefinedrange of values.
 27. The method according to claim 26, furthercomprising assessing PPG signal quality by means of a kurtosis orskewness method.
 28. The method according to claim 23, furthercomprising calculating an artefact-free derived PPG signal (PPGd). 29.The method according to claim 23, wherein the reliability rangesubstantially corresponds to a predefined PPG signal template.
 30. Themethod according to claim 23, wherein filtering the PPG signal comprisesrejecting non-ideal pulses.
 31. The method according to claim 23,further comprising re-evaluating the PPG signal by comparing the PPGsignal with previously stored values of PPG signals.
 32. (canceled) 33.The method according to claim 28, further comprising extracting featuresfrom the PPGd signal, wherein extracting features comprises: providing aPPGd signal having a plurality of epochs comprising pulses; andseparating the pulses of each epoch of the PPGd signal.
 34. The methodaccording to claim 33, further comprising for each pulse: extracting afalling edge (ePW(i)) of the pulse; discarding beginning and end tailsof each ePW(i); calculating a first derivative of each ePW(i); findingzero crossings (zCx) of each ePW; determining a location of the zerocrossings (zCx); retrieving all dicrotic notch/incisura positions; andrepeating the steps for all pulses of the PPGd signal. 35.-43.(canceled)
 44. A method for calculating blood oxygen level (SpO₂)comprising: contacting the skin with the wrist-watch back case of atimekeeping device according to claim 1; providing a PPGd signal;separating the PPGd signal into pulse waves; calculating the absorptionand emission peaks; calculating RatioR from the absorption and emissionpeaks; calculating extinction coefficients of oxyhemoglobin anddeoxyhemoglobin; and calculating a unique wave propagation calibrationcoefficient (a).
 45. (canceled)
 46. A method for calculating bloodpressure (BP) comprising: ensuring an ideal noise free environment,contacting the skin with the wrist-watch back case of a timekeepingdevice according to claim 1; estimating the BP; comparing the estimatedBP with a predetermined range, and generating a message to inform theuser to measure the BP with conventional sphygmomanometer when theestimated BP is out of the predetermined range. 47.-50. (canceled)
 51. Awatchband to be attached around a wrist of a user in an adjustablemanner for non-invasive measurements of biomarkers, the watchbandcomprising: a textile layer having perforations to adapt the degree offixation; coupling elements for coupling the watchband to a watch face,a buckle coupled to an end of the wristband, the buckle having a frameand a pivoting prong coupled to the frame, and a tightening mechanismfor obtaining a predefined fixation on the wrist, the tighteningmechanism comprising a ratchet gear having locking teeth in apredetermined angular range; a pivoting strut to engage the ratchetgear, and wherein the tightening mechanism is arranged at a side of thebuckle of a wristband. 52.-54. (canceled)
 55. A timekeeping devicecomprising: a wristband according to claim 51; and a wrist-watch backcase according to claim
 1. 56. (canceled)
 57. A system for non-invasivemeasurements of biomarkers, comprising: a wrist-watch back caseaccording to claim 1, an interface module, and a mobile device forcontrolling signal acquisition procedure, acquisition mode andacquisition parameters. 58.-59. (canceled)